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Jeanette Arnold, MSN, C-FNP Instructor Division of Clinical Allergy, Immunology and Rheumatology University of Mississippi Medical Center Jackson, Mississippi,

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Presentation on theme: "Jeanette Arnold, MSN, C-FNP Instructor Division of Clinical Allergy, Immunology and Rheumatology University of Mississippi Medical Center Jackson, Mississippi,"— Presentation transcript:

1 Jeanette Arnold, MSN, C-FNP Instructor Division of Clinical Allergy, Immunology and Rheumatology University of Mississippi Medical Center Jackson, Mississippi, USA JLArnold@umc.edu Asthma Update

2 AAFA No other disclosures or industry affiliations Disclosures

3 At the conclusion of this presentation, participants should: 1. Be familiar with recent studies on the use of anticholinergic medications in asthma 2. Be able to discuss the relationship between ICS and growth in children 3. Be able to interpret current data on acetaminophen and asthma Objectives

4 Where weve been: Homogenous asthma manifested by bronchospastic obstruction…mucus, inflammation Owls blood in wine, tobacco, coffee/tea, Indian hemp, ether or opium; then systemic steroids, theophylline and SABA… then ICS with and without LABA Control based on lung function and symptomatology All asthmatics are not created equally

5 Where were going: Asthma is heterogeneous- Differences in pathology, symptomatology, response to therapy and prognosis (Lotvall, JACI 2011) 70-95% w/ mild to moderate ds- managed with ICS and beta 2 5-35% fail standard tx: severe disease or refractory asthma (Morjaria et al, COACI 2011) Mixed inflammatory: Cells (neutrophils, eosinophils and basophils) Cytokines (interleukin [IL]-4, and chemokines) B-cells and activated T-cells [Th1, Th2, Th17] (Durrani & Busse,Chest, 2011) All asthmatics are not created equally

6 Influence of co-morbidities Obesity, CRS, GERD- Atopy not as big an influence as we thought (Turato AJRCCM 2008) Routine ICS fail to alter remodeling (Guilbert NEJM 2006, Murray Lancet 2006) Definition of control? - dual domains: QOL, symptoms and exacerbations Preservation (or loss ) of lung function, exacerbations and medication risk/SE (Durrani, 2011) All asthmatics are not created equally

7 Asthmatics w/ 1° neutrophilic inflammation are: More steroid resistant than eosinophilic asthmatics. More likely to have severe asthma with more acute exacerbations ( Wenzel, 2006; Gibson, 2009 ).20062009 Asthmatics who smoke are more likely to have asthma resistant to low dose ICS (Tomlinson et al., 2005; Lazarus et al., 2007).20052007 Asthma Heterogeneity and Phenotyping

8 Current step up tx from a low dose ICS: Either double the glucocorticoid dose or add a LABA (or leukotriene inhibitor) ICS have a relatively flat dose–response curve; controversial LABAs are controversial (B16-Arg/Arg) Taking a new look at an old drug: anticholinergics Smith, L. Anticholinergics for Patients with Asthma? New Engl J Med Oct., 2010; 363:1764-1765 First Things First

9 Peters, SP. et al. 2010, N. Engl. J. Med. 363, 1715-1726 200 poorly controlled asthmatics 3 arms: tiotropium + ICS salmeterol + ICS doubled the ICS per NAEPP As effective as adding salmeterol and more effective than doubling the ICS Tiotropium bromide step-up therapy for adults with uncontrolled asthma

10 Vogelmeier, C., et al., N Engl J Med. March 2011; 364:1093-1103 1-year, randomized, D-B, D-D, parallel-group Compared # of moderate or severe exacerbations in pts with moderate- to-very-severe COPD & hx of exacerbations in the preceding 12 months 7, 376 patients randomly assigned Tiotropium (n=3707) or Salmeterol (n= 3669) Tiotropium more effective than Salmeterol: Increased time to first exacerbation (187 days vs 145) Reduced annual # of exacerbations (0.09 vs 0.13) Incidence of adverse events similar (64 deaths/1.7% vs 78/2.1%) Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD

11 Kerstiens, H. et al., JACI, Aug 2011; 128 (2): 308-314 R, D-B, P-C crossover study; 107 pt., 54% F, mean 55 y/0 1º endpoint peak FEV1 3 arms: tx for eight weeks each Original meds (@ least ICS + LABA) + tiotropium 5 mcg + tiotropium 10 mcg + placebo Both doses of tiotropium once daily significantly improves lung function…in pt. w/ inadequately controlled severe, persistent asthma. Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial

12 Bateman ED, et al. JACI 2011 Aug; 128 (2): 315-322 16 week, D-B,D-D, P-C trial in 388 (B16-Arg/Arg) asthmatics not controlled on ICS alone; 18-67 yr After 4 week run in w/ BID salmeterol MDI, Randomized 1:1:1 & compared salmeterol + ICS (n=134) tiotropium + ICS (n=128) placebo + ICS (n= 125) Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma

13 Measured weekly AM PEF: 1º endpoint PEF Tiotropium -3.9 ± 4.87 L/min Salmeterol - 3.2 ± 4.64 L/min Placebo -24.6 ± 4.84 L/min Tiotropium and salmeterol were roughly equivocal Both were significantly more effective than placebo Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma

14 Barnes, Peter J. w/ NHLBI Expert Review article (Expert Rev. Respir. Med 5 (3), 297-300 (2011) @ www.expert-reviews.comwww.expert-reviews.com First triple inhaler containing formoterol, tiotropium and ciclesonide (Triohale, Cipla) marketed in India Too soon to tell, but data might support using tiotropium as add on therapy in certain phenotypes/severe asthmatic poor responders Future for triple inhalers?

15 2000 N Engl J Med; Agertoft and Pederson 211 children over 10 years- 142 w budesonide 18 control pt w/asthma never ICS 51 siblings w/o asthma Children w/asthma treated w/ long term budesonide reached nl adult height 2011 JACI; Guilbert et al. Are certain subgroups of children @ higher risk from ICS? Children 2 and 3 years old w/ recurrent wheezing (high risk for asthma) Two arms: fluticasone x 2 years vs placebo Followed for 2 years after ICS d/cd Overall, no diff. in linear growth b/w ICS or not Children 15 kg Steroid use in growth of children

16 Shaheen, S. et al. Prenatal and infant acetaminophen exposure, antioxidant gene polymorhpisms and childhood asthma. JACI, Dec. 2010; 126(6): 1141-1148. British Avon Longitudinal Study of Parents and Children (ALSPAC) 14000 children from utero to 8 th year Mother reported acetaminophen exposure in utero and early childhood, hx of early wheezing, allergy and asthma s/s, environmental exposures and family lifestyles. PFT, blood or skin tests for allergies and genetic testing of mother and child b/w ages 7 and 8 yrs. Longitudinal association w/ childhood asthma was limited to children who had wheezed in infancy- Suggests casual relationship Acetaminophen and Atopy: Causality or Commonality?

17 Marquis, A. et. al, JACI Jan. 2011; 127(1): 270-272 1293 young adults cured from CA from Swiss Childhood Cancer Registry 16 @ time of survey;@ least 5 yrs post diagnosis PMH of asthma, frequency and type of analgesics: Paracetamol alone Nonaspirin NSAIDs alone ASA alone Or different combinations of these three Found a positive association b/w non-ASA NSAIDs and asthma = paracetamol and asthma; if this is causal, not limited to acetaminophen. Most likely explanation is confounding by indication- more studies needed Paracetamol, non-steroidal anti-inflammatory drugs, and risk of asthma in adult survivors of childhood cancer

18 Schnabel, E. and Heinrich, J.; JACI Nov. 2010; 126(5): 1071-1073. 3097 healthy full term infants under Influences of Lifestyle-related Factors on the Immune System and the Development of Allergies in Childhood (LISA) Birth – 6 years; monthly diaries of febrile illnesses, type & medication use Measured IgE to common inhalants at 2 and 6 years age by CAP-RAST < 5% of these children were tx with anything other than acetaminophen Children with asthma had > fever than non-asthmatics No correlation b/w allergic sensitization and acetaminophen Suggests increased incidence of URI and febrile illnesses in asthmatic children more likely source of association. Respiratory tract infections and not paracetamol medication during infancy are associated with asthma development in childhood

19 Medication/ therapy Mechanism of action Summary of trial results Golimumab and Etanercept TNF-a and TNFR2 DBPC- lacked efficacy; terminated due to > SE; no further studies planned MepolizumabMonoclonal Ab (Anti-IL-5) antagonizes eosinophilic pathway 2 DBPC- decreased eosinophilia with < exacerbations- further studies CAT-354/IMA-638/QAX576Monoclonal Ab (Anti-IL 13)Initial reports suggest efficacy; phase 2 studies DaclizumabAnti-CD25; antagonizes IL-21 study; 115 pt.; small but signif. Improvements; no SE; needs more study MasitinibTyrosine kinase inhibitor (c-kit and PDGF receptors) Pilot study; mixed results with lots drop outs RE drug SE and poor outcome Upcoming therapies under investigation

20 Medication/ therapy Mechanism of action Summary of trial results AMG 317IL-4 receptor alpha chain used by IL-4 and IL-13; high affinity IL-4 a receptor binder No signif. diff in 1º or 2º endpoints; well tolerated; needs more study AltrakinceptSolubilized IL-4 receptor fragment; blocks IL-4 Went to phase 3 trial; failed to show efficacy PascolizumabMonoclonal Ab antagonizes IL-4 Discontinued phase 2 trial; failed to show efficacy PitrakinraIL-4 mutant protein; binds to alpha IL-4 subunit Inhaled form promising; phase 2a trial Upcoming therapies under investigation

21 30 year old male born early @ 2#; early wheezer; frequent URI with normal immune system work up- lost to FU age 5-15 yrs. Formally diagnosed with asthma as teenager 3 hospitalizations over the last 5 years; 1 ICU (6 months ago)- no intubations Maximum ICS with LABA combination, leukotriene inhibitor and PPI; pharmacy records indicate appropriate med. refill rates Skin test mildly positive to DM but not impressive Co-morbidities include GERD, obesity and nasal polyposis Labs: normal CBC with exception of mildly elevated peripheral blood eosinophils, normal CMP but moderately elevated IgE Case study

22 You tell him: 1. Only if you take your medications! Your lack of asthma control indicates youre non-compliant 2. Only if you lose weight! Your obesity makes it impossible to adequately treat you. 3. Hang in there! There is a lot of research currently underway that is specifically targeted towards difficult to control asthmatics and it looks promising. Were gaining more understanding of which therapies are better suited for you and making progress. Lets schedule a visit with your doctor to sit down and discuss options. He asks you if there is any hope for him to live a normal life, stay out of the hospital and play sports with his newborn sons one day…

23 Apter, A. Advances in adult asthma diagnosis and treatment and HEDQ 2010. J Allergy Clin Immunol, 2011, Jan; 127(1): 116-122.127(1 Bateman ED, Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol. 2011 Aug;128(2):315-22.Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. Barnes PJ. Triple inhalers for obstructive airways disease: will they be useful? Expert Rev Respir Med. 2011 Jun;5(3):297-300. No abstract available. PMID: 21702649Triple inhalers for obstructive airways disease: will they be useful? Corren, J., et al. Effects of omalizumab on changes in pulmonary function induced by controlled cat room challenge. J Allergy Clin Immunol. 2011, Feb;127(2):398-405. (www.ncbi.nlm.nih.gov/pubmed/21281870)www.ncbi.nlm.nih.gov/pubmed/21281870 Cox, Linda S., How Safe are the Biologicals in Treating Asthma and Rhinitis? Allergy, Asthma & Clinical Immunology 2009, 5:4 (doi:10.1186/1710-1492-5-4) Resources

24 Durrani, S., Busse, W. ; Biological Therapy for Asthma. Chestnet.org. PCCSU Article | 03.15.11; volume 25 online. Garcia-Marcos, L., et al. Early exposure to acetaminophen and allergic disorders. Curr Opin Allergy Clinic Immunolo. June, 2011; 11(3): 162-173. Gonem S, et al. Evidence for phenotype-driven treatment in asthmatic patients.. Curr Opin Allergy Clin Immunol. 2011 Aug;11(4):381-5. Review. PMID: 21670666Evidence for phenotype-driven treatment in asthmatic patients. Guilbert, T., et al. Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone. JACI 2011, Nov; 128(5): 956-963. Kerstjens HA, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011 Aug;128(2):308-14. Epub 2011 Jun 2.Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. Resources

25 Marquis, A., et al. Paracetamol, nonsteroidal anti-inflammatory drugs and the risk of asthma in adult survivors of childhood cancer. J Allergy Clin Immunol 2011 Jan; 127 (1): 270-272. Maneechotesuwan K, et al. Bronchodilator effect of Ipraterol on methacholine- induced bronchoconstriction in asthmatic patients. J Med Assoc Thai. 2011 Feb;94 Suppl 1:S66-71.Bronchodilator effect of Ipraterol on methacholine- induced bronchoconstriction in asthmatic patients. Morjaria, J, et al. Stratified Medicine in Selecting Biologics for the Treatment of Severe Asthma. Curr Opin Allergy Clini Immunolo. 2011; 11(1): 58-63. (www.medscape.com/viewarticle/735050)www.medscape.com/viewarticle/735050 Shaheen, S., et al. Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma. J Allergy Clin Immunol. 2010 Dec; 126(6): 1141-1148. (http://www.jacionline.org/article/S0091-6749(10)01408- 9/fulltext) 126(6http://www.jacionline.org/article/S0091-6749(10)01408- 9/fulltext) Schnabel, E. Heinric, J. Respiratory tract infections and not paracetamol medications during during infancy are associated with asthma development in childhood. JACI. 2010 Nov; 126 (5) 1071-1073.126 (5 Resources

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